The intrinsic limits of conventional cancer therapies prompt the development of a new technology for a more effective and safer cancer treatment. The bioresponsive delivery technique has recently emerged as an innovative strategy to overcome multiple barriers in the systemic delivery of nanoparticle (NP)-based therapeutics. However, some issues especially the tumor penetration-retention balance have not been completely solved, which may induce the suboptimal therapeutic effect. Herein, we developed a new multifunctional sharp pH-responsive NP platform for targeted drug delivery and effective cancer therapy. This NP platform is made of the sharp pH-responsive poly(2-(diisopropylamino)ethylmethacrylate) (PDPA) polymer as the inner core, amphiphilic lipid-poly(ethylene glycol) (lipid-PEG) as the outer shell, and the internalizing RGD (iRGD) peptide encoded on the surface. After anticancer drug loading and then systemic administration, the resulting NP platform shows the following features in one nanostructure: (i) the PEG shell to prolong blood circulation; (ii) the iRGD peptide to enhance tumor targeting and penetration; (iii) a larger particle size (∼80 nm) than that of free drug to ensure long tumor retention; (iv) the sharp endosomal pH response of the PDPA polymer to induce fast intracellular drug release and thus efficient inhibition of tumor growth. Together with facile polymer synthesis and robust NP formulation to enable easy scale-up, the multifunctional NP platform reported herein shows great potential as a new generation nanomedicine for effective cancer treatment.